Pneumonia results from an acute infection of one or more functional elements of the lung, including alveolar spaces and interstitial tissue. In the USA, about 2 million people develop pneumonia each year, and 40,000 to 70,000 of these people die. Pneumonia ranks sixth among all disease categories as a cause of death and is the most common lethal nosocomial (hospital-acquired) infection. Community-acquired pneumonia (CAP) has a significant impact on health care costs in the United States, accounting for an estimated $14 billion per year in direct costs and $9 billion in lost wages. (Lynch J P, Martinez F J. Community-acquired pneumonia. Curr Opin Pulm Med. 1998; 4:162-172). In developing countries, lower respiratory tract infections typically are either the major cause of death or rank second only to infectious diarrhea. (The Merck Manual, Sec. 6, Ch. 73, Pneumonia, 2000).
The condition known as “severe pneumonia” is characterized according to guidelines set forth by various organizations, including the American Thoracic Society (ATS). (Am J Respir Crit Care Med 2001; 163:1730-1754). For example, the ATS requires at least one major criterion, such as a need for mechanical ventilation or septic shock, in addition to other criteria for a diagnosis of severe pneumonia. Generally, severe pneumonia can result from acute lung disease, lung inflammatory disease, or any perturbations in lung function due to factors such as inflammation or coagulation. A diagnosis of severe CAP is based on a patient being admitted to an ICU specifically for pneumonia. Epidemiologically, this patient population comprises approximately 10% of all ICU admissions. Patients in the ICU with pneumonia have the highest mortality of all CAP patients (30% to 40%) compared with less than 15% for general hospitalized patients with CAP.
Each year in the United States, community-acquired pneumonia (CAP) is diagnosed in approximately 4 million adults, with as many as 600,000 requiring hospitalization. Fine et al., N. Engl. J. Med. 336, 243-50, 1997. Overall, the incidence of CAP increases with age, with the greatest prevalence found in those aged 65 years and older. Marston et al., Arch Intern Med. 1997; 157:1709-1718. The incidence is also increased in patients with comorbidities, such as chronic obstructive pulmonary disease, asthma, diabetes mellitus, alcoholism, immunosuppression, renal insufficiency, chronic liver disease, and cardiac disease. Marrie, Curr Opin Pulm Med. 1996; 2:192-197; Niedermann et al., Am Rev Respir Dis. 1993; 148:1418-1426.
Pneumonia is the leading cause of death from infection in the United States and the sixth leading cause of death overall. The pneumonia-related mortality rate increased by 22% from 1979 to 1992, with elderly patients (65 years and older) accounting for 89% of all pneumonia-related deaths in 1992. See Pneumonia and influenza death rates—United States, 1979-1994 [published correction appears in MMWR. 1995; 44:782]. MMWR. 1995; 44:535-537. Fine and colleagues (1997) reported that certain coexisting illnesses (neoplastic disease, congestive heart failure (CHF) cerebrovascular disease, renal disease, and liver disease) and certain physical examination findings (altered mental status, increased heart rate, increased respiratory rate, decreased systolic blood pressure, and abnormally low or elevated temperatures) are also associated with increased CAP-related mortality. In addition, CAP has a significant impact on health care costs in the United States, accounting for an estimated $14 billion per year in direct costs and $9 billion in lost wages. Lynch & Martinez, Curr Opin Pulm Med. 1998; 4:162-172.
Tissue factor pathway inhibitor (TFPI) is a protein and a serine protease inhibitor present in mammalian blood plasma. Thomas, Bull. Johns Hopkins Hosp. 81, 26 (1947); Schneider, Am. J. Physiol. 149, 123 (1947); Broze & Miletich, Proc. Natl. Acad. Sci. USA 84, 1886 (1987). TFPI is also known as tissue factor inhibitor, tissue thromboplastin inhibitor, Factor III inhibitor, extrinsic pathway inhibitor (EPI), and lipoprotein-associated coagulation inhibitor (LACI). The name “tissue factor pathway inhibitor” (TFPI) was accepted by the International Society on Thrombosis and Hemostasis on Jun. 30, 1991.
Blood coagulation activation is the conversion of fluid blood to a solid gel or clot. In addition, consumption of the coagulation proteases leads to excessive bleeding. The main event is the conversion of soluble fibrinogen to insoluble strands of fibrin, although fibrin itself forms only 0.15% of the total blood clot. This conversion is the last step in a complex enzyme cascade. The components (factors) are present as zymogens, inactive precursors of proteolytic enzymes, which are converted into active enzymes by proteolytic cleavage at specific sites. Activation of a small amount of one factor catalyzes the formation of larger amounts of the next, and so on, resulting in an amplification that results in an extremely rapid formation of fibrin.
Coagulation is believed to be initiated by vessel damage which exposes factor VIIa to tissue factor (TF), which is expressed on cells beneath the endothelium. The factor VIIa-TF complex cleaves factor X to factor Xa and cleaves factor IX to factor IXa. TFPI binds to both factor VIIa and factor Xa. The complex formed between TFPI, factor VIIa (with its bound TF), and factor Xa inhibits further formation of factors Xa and IXa, required for sustained hemostasis. Broze, Jr., Ann. Rev. Med. 46:103 (1995).
Activation of the coagulation cascade by bacterial products, including endotoxins, introduced directly into the bloodstream can result in extensive fibrin deposition on arterial surfaces, as well as depletion of fibrinogen, prothrombin, factors V and VIII, and platelets. In addition, the fibrinolytic system is stimulated, resulting in further formation of fibrin degradation products.
At the same time as coagulation activation is apparently initiated by bacterial products (e.g., endotoxin), contravening mechanisms also appear to be activated by clotting, namely activation of the fibrinolytic system. Activated Factor XIII converts plasminogen pro-activator, to plasminogen activator that subsequently converts plasminogen to plasmin, thereby mediating clot lysis. The activation of plasma fibrinolytic systems may therefore also contribute to bleeding tendencies.
Endotoxemia is associated with an increase in the circulating levels of tissue plasminogen activator inhibitor (PAI). This inhibitor rapidly inactivates tissue plasminogen activator (TPA), thereby hindering its ability to promote fibrinolysis through activation of plasminogen to plasmin. Impairment of fibrinolysis may cause fibrin deposition in blood vessels, thus contributing to the DIC associated with septic shock.
Efforts are ongoing to identify satisfactory interventions for the prevention or treatment of severe pneumonia and associated coagulopathies. An agent that interrupts the coagulation pathway is not necessarily effective as a therapeutic or a prophylactic treatment of severe pneumonia. For example, heparin is a commonly used anticoagulant. However, management of the use of heparin has been difficult because heparin can induce excessive bleeding and has been found to attenuate coagulation abnormalities but not offer a survival benefit. See for example, Aoki et al., “A Comparative Double-BLIND randomized Trial of Activated Protein C and Unfractionated Heparin in the Treatment of Disseminated Intravascular Coagulation,” Int. J. Hematol. 75, 540-47 (2002). Several clinical trials, mainly in meningococcal endotoxemia where fulminating DIC is a prominent feature, have failed to demonstrate reduction of mortality in sepsis by heparin treatment. See, for example, Corrigan et al., “Heparin Therapy in Septacemia with Disseminated Intravascular Coagulation. Effect on Mortality and on Correction of Hemostatic Defects,” N. Engl. J. Med., 283:778-782 (1970); Lasch et al., Heparin Therapy of Diffuse Intravascular Coagulation (DIC)”, Thrombos. Diathes. Haemorrh., 33:105 (1974); Straub, “A Case Against Heparin Therapy of Intravascular Coagulation”, Thrombos. Diathes. Haemorrh., 33:107 (1974).
Administration of recombinant human ala-TFPI (a TFPI analog) has been shown to improve survival rates in animal models of sepsis. See, e.g., U.S. Pat. No. 6,063,764. As an endogenous protein, TFPI is well tolerated. TFPI administration by intravenous infusion or subcutaneous injection has been shown to reduce clotting ability, which is manifested as increased prothrombin time (PT). In studies of animals and humans, prolongations of PT were linearly related to the increase of plasma TFPI. A. A. Creasey, Sepsis 3:173 (1999).
There remains a need in the art for treatment approaches that will inhibit the lethal effects of severe pneumonia and simultaneously minimize potentially serious side effects.